What type of inhibitor is oxamate

Targeting cancer metabolism to develop human lactate dehydrogenase h LDH 5 inhibitors. Drug Discovery Today , 23 7 , Oliveira , Ivana M. Marzano , Carlos B. Topological control of supramolecular crystal structures of phenylene bis-monothiooxamate derivatives and in vitro anticancer activity.

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Analytical Biochemistry , 2 , Small-molecule inhibitors of human LDH5. Accordingly, the inhibition of OXA on AAT might have deleterious effects on the glucose metabolism of cells of the liver, skeletal muscle, and adipose tissue. Aerobic glycolysis is a hallmark of malignant tumor metabolism, and OXA can inhibit the activity of LDH and decrease lactate production in cancer cells [ 2 , 3 ].

It has been reported that OXA has anti-cancer properties in vitro and in animals in vivo [ 1 , 5 , 6 , 49 , 50 ]. However, OXA is a competitive inhibitor of LDH at high concentrations, which limits its therapeutic potential in clinical practice [ 49 ]. Oxamic acid derivatives are developing, which are being considered as a potential drug for the treatment of malignant tumors in the future [ 7 , 51 ].

Therefore, we consider that Oxamic acid derivatives may also be a potential drug for the treatment of type 2 diabetes. Analyzed the data: WY MW. Wrote the paper: MW. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Abstract Oxamate OXA is a pyruvate analogue that directly inhibits the lactate dehydrogenase LDH -catalyzed conversion process of pyruvate into lactate.

Data Availability: All relevant data are within the paper Funding: The authors have no support or funding to report. Introduction Oxamate OXA is a pyruvate analogue that directly inhibits the conversion of pyruvate into lactate by lactate dehydrogenase LDH [ 1 ].

Study design Thirty-five four-week-old male mice were randomly divided into 7 groups numbered as groups I—VII with five mice in each group. Health score Six criteria including activity, posture, dehydration, pelage, and skin wounding were used to assess the health of the mice Table 1.

Download: PPT. Blood biochemical marker measurements Blood glucose concentrations were determined using a glucometer LifeScan Inc. Measurements of tissue lactate production Adipose tissue and skeletal muscle samples were rapidly thawed, blotted dry, and weighed.

Results Health condition and food intake All of the mice were healthy a health score of 0 throughout the study. Effects of OXA on weight gain Changes in the body weight of all the studied mice during the 12 week period are shown in Fig 2.

Fig 8. Effects of OXA on tissue lactate production and serum lactate levels. Fig 9. Effects of OXA on serum levels of lipid and pro-inflammatory cytokines. Fig Effects of OXA on genes related to the insulin signaling pathway in skeletal muscle.

Effects of OXA on islet morphology and insulin expression. References 1. Warburg effect in chemosensitivity: targeting lactate dehydrogenase-A re-sensitizes taxol-resistant cancer cells to taxol.

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Inhibitors of lactate dehydrogenase isoforms and their therapeutic potentials. Curr Med Chem. Plasma lactate con-centration in obesity and type 2 diabetes. Diabetes Metab. Insulin resistance in obesity is associated with elevated basal lactate levels and diminished lactate appearance following intravenous glucose and insulin.

Risk factors for type 2 non-insulin-dependent diabetes mellitus. Thirteen and one-half years of follow-up of the participants in a study of Swedish men born in Mechanism of increased gluconeogenesis in noninsulin-dependent diabetes mellitus.

Role of alterations in systemic, hepatic, and muscle lactate and alanine metabolism. J Clin Invest ; — Am J Physiol Endocrinol Metab. Then, to confirm the LDH inhibition effect of oxamate as previously reported 18 , 19 , a commercially available kit was used to determine the intracellular LDH enzyme activity after treatment with different doses of oxamate. The results showed that oxamate significantly decreased LDH activity Fig.

A Cells were exposed to different concentrations of oxamate for 24, 48 and 72 h, in well plates, and the effects on cell viability were tested by MTT assay. B Cells were treated with 0, 20, 50 and mM oxamate for 24 h, then intracellular LDH enzyme activity was determined using a commercially available kit. LDH, lactate dehydrogenase. Since a great majority of anticancer agents act on the cell cycle and its checkpoint 23 , alterations in cell cycle distribution after oxamate treatment were investigated in NPC cancer cells.

However, the S phase fractions did not change significantly in both cell lines. In addition, it was noteworthy that there was a significant increase in the percentage of cells in the sub-G 1 phase after treatment with oxamate.

A Cells were exposed to 0, 20, 50 and mM oxamate for 24 h, and then cells were stained with propidium iodide and analyzed using flow cytometry. We demonstrated that LDH inhibition by oxamate impaired cell growth and increased the sub-G 1 fraction in both cell lines. After the h treatment with oxamate, the percentages of early and late apoptotic cells were increased in a dose-dependent manner Fig. Next, western blot analysis was utilized to determine the changes in expression of apoptosis-related proteins.

The results indicate that oxamate induces apoptosis via caspase-3 activation and the mitochondrial pathway in NPC cells. A Cells were treated with 0, 20, 50 and mM oxamate for 48 h, and then cells were stained with Annexin V-FITC and propidium iodide and analyzed using flow cytometry. B Western blot analysis was employed to detect the expression of Bax, Bcl-2, pro-caspase-3 and cleaved caspase-3, proteins related to apoptosis through the mitochondrial pathway. To further explore the mechanisms involving the inhibitory effect induced by oxamate in NPC cells, we determined the changes in ROS levels after oxamate treatment, which play an important role in the mitochondrial apoptotic pathway.

ROS levels were increased to 1. Similarly, there was an 1. To examine the role of ROS generation in the oxamate-induced growth inhibitory effect, oxamate-treated cells were incubated simultaneously with 10 mM N-acetylcysteine, a specific scavenger of ROS. Induction of ROS levels by oxamate and its role in cell survival.

B Growth inhibitory effect of oxamate was recovered by NAC. Cells were treated with different concentrations of oxamate combined with 10 mM NAC or without for 24 h in well plates. Cell viability was then determined by MTT assay.

Radiotherapy is the main treatment for NPC patients at present. The sensitivity enhancement ratios SERs were 1. A Oxamate increases IR-induced apoptosis. Cells were pretreated with 20 mM oxamate for 24 h and exposed to 6 Gy X-ray irradiation. After incubation for another 24 h, cells were stained with Annexin V and propidium iodide and analyzed using flow cytometry. IR alone. B Effects of oxamate on radiation survival curves.

Cells were pretreated with 20 mM oxamate for 24 h and exposed to 0—9 Gy X-ray irradiation. Cells were incubated for another 2 weeks before fixation, staining and assessment of colony formation.

Survival curves were constructed according to the linear quadratic model. Con, control; Oxa, oxamate; IR, irradiation. Finally, we examined whether oxamate inhibits tumor growth in vivo and its effects when combined with irradiation treatment.

Moreover, combined treatment with oxamate and irradiation significantly improved the growth inhibitory effect when compared to either oxamate alone or irradiation alone. A small decrease in body weights of the mice was noted following treatment with oxamate and irradiation. However, the decrease had no statistical significance when compared to the mice treated with oxamate alone.

Combined treatment with oxamate and irradiation effectively inhibits tumor growth in vivo. The control group received equal volumes of PBS i. However, the detailed mechanism remains largely unclear. In this study, we demonstrate that oxamate inhibits the viability of human gastric cancer cells in a dose- and time-dependent manner.

In addition, treatment with oxamate induces protective autophagy in gastric cancer cells.